U.S. patent number 9,763,600 [Application Number 13/577,965] was granted by the patent office on 2017-09-19 for nitric oxide measurement method and apparatus.
This patent grant is currently assigned to KONINKLIJKE PHILIPS N.V.. The grantee listed for this patent is Hans Willem Van Kesteren, Teunis Johannes Vink. Invention is credited to Hans Willem Van Kesteren, Teunis Johannes Vink.
United States Patent |
9,763,600 |
Van Kesteren , et
al. |
September 19, 2017 |
Nitric oxide measurement method and apparatus
Abstract
There is provided a method of determining at least one parameter
value relating to nitric oxide, NO, production in the lower
respiratory tract of a subject, the method comprising obtaining a
plurality of measurements of NO levels in exhaled air and air flow
rate during multiple exhalations of a subject performing tidal
breathing; analyzing the plurality of measurements to identify
exhalations where the NO produced in the lower respiratory tract
dominates the NO contribution from other sources; determining at
least one parameter value relating to NO in the lower respiratory
tract of the subject from the measurements of NO levels and/or air
flow rate obtained during the identified exhalations.
Inventors: |
Van Kesteren; Hans Willem
(Eindhoven, NL), Vink; Teunis Johannes (Eindhoven,
NL) |
Applicant: |
Name |
City |
State |
Country |
Type |
Van Kesteren; Hans Willem
Vink; Teunis Johannes |
Eindhoven
Eindhoven |
N/A
N/A |
NL
NL |
|
|
Assignee: |
KONINKLIJKE PHILIPS N.V.
(Eindhoven, NL)
|
Family
ID: |
44141023 |
Appl.
No.: |
13/577,965 |
Filed: |
February 10, 2011 |
PCT
Filed: |
February 10, 2011 |
PCT No.: |
PCT/IB2011/050566 |
371(c)(1),(2),(4) Date: |
August 09, 2012 |
PCT
Pub. No.: |
WO2011/101776 |
PCT
Pub. Date: |
August 25, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120310104 A1 |
Dec 6, 2012 |
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Foreign Application Priority Data
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Feb 17, 2010 [EP] |
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10153795 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B
5/082 (20130101); A61B 5/083 (20130101) |
Current International
Class: |
A61B
5/083 (20060101); A61B 5/08 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2009001275 |
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Dec 2008 |
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WO |
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2011013046 |
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Feb 2011 |
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WO |
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Other References
Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing and
Allied Health, Apr. 2003, Elsevier Health Sciences, 7th Edition.
cited by examiner .
P. Condorelli et al., "Characterizing Airway and Alveolar Nitric
Oxide Exchange During Tidal Breathing Using a Three-Compartment
Model", J. Appl Physiol 96:, Jan. 16, 2004, pp. 1832-1842. cited by
applicant .
ATS/ERS Recommendations for Standardized Procedures for the Online
and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide
and Nasal Nitric Oxide 2005:, Am. J. Respir. Crit. Care Med. vol.
171, pp. 912-930, 2005. cited by applicant .
Tsoukias, N. M. et al., "A Two-Compartment Model of Pulmonary
Nitric Oxide Exchange Dynamics", J. Appl. Physiol. vol. 85, pp.
653-666, 1998. cited by applicant.
|
Primary Examiner: Cheng; Jacqueline
Assistant Examiner: Portillo; Jairo
Attorney, Agent or Firm: Haas; Michael W.
Claims
The invention claimed is:
1. A method of determining at least one parameter value relating to
nitric oxide, NO, production in the lower respiratory tract of a
subject, using an apparatus including a NO sensor, a flow rate
sensor and a processor, the method comprising: obtaining, with the
NO sensor and the flow rate sensor, a plurality of measurements of
NO levels in exhaled air and air flow rate during multiple
exhalations of a subject performing tidal breathing; analyzing,
with the processor, the plurality of measurements to identify
exhalations where the NO produced in the lower respiratory tract
dominates the NO contribution from other sources; wherein analyzing
comprises: separating individual exhalations into a plurality of
exhalation parts; for each individual exhalation part, determining
values for a flow independent parameter, wherein the flow
independent parameter is an airway wall concentration of NO or a
maximum airway wall flux of NO, using the measurements of NO levels
and flow rate obtained during that exhalation part; for the
individual exhalation parts, determining the average value of the
determined values for the flow independent parameter; identifying
an exhalation part having the lowest average value; discarding any
exhalation part whose average value for the flow independent
parameter deviates from the lowest average value by more than a
threshold value; and identifying the exhalation parts remaining as
exhalations where the NO produced in the lower respiratory tract
dominates the NO contribution from other sources; determining, with
the processor, the flow independent parameter from the measurements
of NO levels and/or air flow rate of each of the exhalation parts
remaining; and outputting, with the processor, the determined
values of the flow independent parameter of the exhalation parts
remaining.
2. A method as claimed in claim 1, wherein determining values for
the flow independent parameter for each individual exhalation part
comprises using a model describing the flow dependence of NO levels
in exhaled air.
3. A method as claimed in claim 2, wherein the model comprises one
of a two-compartment model, three-compartment model, or a trumpet
model.
4. A method as claimed in claim 2, wherein the model is a
two-compartment model in which the exhaled NO concentration, CE, is
given by ee ##EQU00006## where C.sub.alv is the alveolar
concentration of NO, D.sub.aw is the airway diffusion coefficient,
V is the air flow rate, the ratio of C.sub.alv/C.sub.w and the
value of D.sub.aw are set to constant values and wherein the step
of analyzing comprises determining values for the wall
concentration, C.sub.w, from the measurements of the NO level and
air flow rate.
5. A method as claimed in claim 4, wherein the ratio of
C.sub.alv/C.sub.w and D.sub.aw in the model are set to respective
constant values based on a population value or a previous personal
value for the subject.
6. A method as claimed in claim 2, wherein the model is a trumpet
model in which the exhaled NO concentration, C.sub.E, is given by
.times..times..times. ##EQU00007## where {dot over (V)} denotes the
air flow rate, D.sub.ax the axial diffusion constant for Nitric
Oxide, and c.sub.3 and c.sub.4 are positive constants and wherein
the step of analyzing comprises determining values for the maximum
airway wall NO flux, J.sub.aw, from the measurements of the NO
level and air flow rate.
7. A method as claimed in claim 6, wherein the parameter D.sub.ax
is a constant value and c.sub.3 and c.sub.4 are set to respective
constant values based on a population value or a previous personal
value for the subject.
8. A method as claimed in claim 1, wherein the step of analyzing
comprises: for the individual exhalation parts, calculating the
spread of the determined values for the flow independent parameter;
and discarding any exhalation part where the calculated spread
deviates from a predetermined value by more than a threshold value
is discarded; wherein the step of determining the average value of
the determined values for the flow independent parameter uses the
exhalation parts remaining after discarding the exhalation parts
whose spread deviates.
9. A method as claimed in claim 8, wherein the threshold value is
determined based on the noise in the measurements of air flow rate
and NO level.
10. A tangible non-transitory computer program product comprising
computer readable code configured to cause a computer, processor or
computer system to perform the method claimed in claim 1.
11. An apparatus for determining a value for at least one parameter
relating to nitric oxide, NO, production in the lower respiratory
tract of a subject, the apparatus comprising: an NO sensor for
taking a plurality of measurements of the level of NO in air
exhaled by the subject during multiple exhalations of a tidal
breathing manoeuvre; a flow rate sensor for taking a plurality of
measurements of the flow rate of air exhaled during the multiple
exhalations of the tidal breathing manoeuvre; and a processor that
is configured to receive the measurements of NO level and flow
rate, analyze the measurements to identify exhalations where the NO
produced in the lower respiratory tract dominates the NO
contribution from other sources, wherein analyzing the measurements
comprises: separating individual exhalations into a plurality of
exhalation parts; for each individual exhalation part, determining
values for a flow independent parameter, wherein the flow
independent parameter is an airway wall concentration of NO or a
maximum airway wall flux of NO, using the measurements of NO levels
and flow rate obtained during that exhalation part; for the
individual exhalation parts, determining the average value of the
determined values for the flow independent parameter; identifying
an exhalation part having the lowest average value; discarding any
exhalation part whose average value for the flow independent
parameter deviates from the lowest average value by more than a
threshold value; and identifying the exhalation parts remaining as
exhalations where the NO produced in the lower respiratory tract
dominates the NO contribution from other sources; determining, the
flow independent parameter from the measurements of NO levels
and/or air flow rate of each of the exhalation parts remaining; and
outputting, with the processor, the determined values of the flow
independent parameter of the exhalation parts remaining.
12. An apparatus as claimed in claim 11, wherein the processor is
configured to analyze the measurements by: for the individual
exhalation parts, calculating the spread of the determined values
for the flow independent parameter; and discarding any exhalation
part where the calculated spread deviates from a predetermined
value by more than a threshold value is discarded; wherein the step
of determining the average value of the determined values for the
flow independent parameter uses the exhalation parts remaining
after discarding the exhalation parts whose spread deviates.
Description
TECHNICAL FIELD OF THE INVENTION
The invention relates to a method and apparatus that measures
nitric oxide (NO) in exhaled air, and in particular to a method and
apparatus that measures nitric oxide (NO) in air exhaled by a
subject performing a tidal breathing manoeuvre.
BACKGROUND TO THE INVENTION
Exhaled nitric oxide (eNO) is a non-invasive marker for airway
inflammation. Inflammation of the airways is present in patients
with asthma, who produce elevated levels of NO in the lower
respiratory tract (bronchi and alveolar part). Therefore, high
values of eNO can be used in combination with other pulmonary tests
for diagnosing asthma. Furthermore, eNO can be used for monitoring
the effectiveness of inhaled corticosteroids (ICS) and in
anti-inflammatory asthma management to titrate ICS dosage.
The standardized method of measuring eNO involves the subject
participating in a single exhalation experiment in which they
breathe out at a fixed flow rate of 50 ml/s and an overpressure of
at least 5 cm H.sub.2O. Recommendations on a standardized method by
the American Thoracic Society and European Respiratory Society are
set out in the paper "ATS/ERS Recommendations for Standardized
Procedures for the Online and Offline Measurement of Exhaled Lower
Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005" American
Journal of Respiratory and Critical Care Medicine Vol. 171, pp
912-930 2005.
An exemplary apparatus for performing a fixed flow rate measurement
is shown in FIG. 1. The apparatus 2 comprises a tube 3 arranged in
a generally `Y` shape with the three ends forming an air inlet 4,
an air outlet 6 and a mouthpiece 8 respectively. A first one-way
valve 10 is provided in the tube 3 between the air inlet 4 and the
mouthpiece 8 and a second one-way valve 12 is provided in the tube
3 between the mouthpiece 8 and the air outlet 6. The one-way valves
10, 12 are configured so that air is drawn through the tube 3 via
the air inlet 4 and mouthpiece 8 when the subject inhales, and air
is passed through the tube 3 via the mouthpiece 8 and air outlet 6
when the subject exhales.
The apparatus 2 also comprises a sensor 14 for measuring levels of
NO in the exhaled air that is connected to a side stream 15 located
between the second one-way valve 12 and the air outlet 6, and a
pressure sensor 16 connected to a side stream 17 that is also
located between the second one-way valve 12 and the air outlet 6.
The pressure sensor 16 measures the pressure resulting from the
exhalation of air through a flow restrictor 20 and provides audio
and/or visual feedback to the subject on whether the flow and
pressure of the exhaled air is appropriate for the measurement
(i.e. a fixed flow rate of 50 ml/s and a pressure of at least 5 cm
H.sub.2O) via a feedback device 18. A processor 19 is connected to
the sensor 14 for processing the NO measurements to determine the
NO level in the, or a portion of the, exhaled air.
The flow restrictor 20 is provided in the air outlet 6 to make it
easier for the subject to reach the required flow and overpressure.
Once the required pressure is achieved, the velum--the soft palate
consisting of muscle fibers sheathed in mucous membrane responsible
for closing off the nasal passages during the act of swallowing and
sneezing--is closed preventing NO from the nasal cavity of the
subject passing into the oral cavity.
A NO filter 22 can be provided in the tube 3 between the air inlet
4 and the first one-way valve 10 that removes NO from the air drawn
into the apparatus 2 from the surrounding environment when the
subject inhales.
However, a problem with this apparatus is that it requires a
constant exhalation flow for a given period of at least 10 seconds,
and this is not simple to perform, in particular for young
children, older subjects, or subjects having difficulty breathing.
Although commercial systems are available based on the apparatus
shown in FIG. 1 that have received approval from the US Food and
Drug Administration (FDA) for standardized eNO measurements on
children aged 7-18 years and adults under supervision of a trained
operator in a physician's office, there is currently no
FDA-approved system for use in young children.
Techniques exist to measure an eNO value during oral tidal
breathing by the subject. Tidal breathing is a much more
straightforward and natural breathing process and thus is much
simpler for the subject to perform than tests using single breath
exhalations at a fixed flow or tests requiring a breath hold for a
certain time. A tidal breathing manoeuvre can be performed by the
subjects themselves without guidance and probably in cooperative
children from the age of three onwards. Tidal breathing generally
involves a breathing frequency of 4-20 breaths per minute for
adults and 20-40 breaths per minute for children and exhaled
volumes of 300-1000 ml per breath for adults and 100-500 ml for
children.
However, a problem with tidal eNO measurement methods is that the
increased flow rates (typically 100-500 ml/s) involved reduces the
concentration of nitric oxide (NO) in the air at the sensor, which
makes the measurement more sensitive to various disturbances like
contamination from NO in the environment or NO from the nasal area
of the subject.
This problem is related to two issues. Firstly, the standardized
fixed flow rate manoeuvre starts with a deep inhalation while tidal
breathing involves a shallower inhalation. This means that only
some of the air from previous inhalations is exchanged in tidal
breathing. Furthermore, during the shorter time involved in a tidal
breathing cycle, the NO in the inhaled air is only partly removed
by the alveoli in the subject's lungs. Therefore, even when NO-free
air is inhaled through the mouth in a tidal breathing manoeuvre,
some inhaled nasal NO can "contaminate" the exhaled air.
Secondly, during the exhalation in the standardized fixed flow rate
manoeuvre, the velum is closed due to the overpressure, so no NO
from the nasal cavity can pass into the oral cavity. However,
during tidal exhalation the velum might be open and NO from the
nasal cavity can diffuse into the air exhaled through the
mouth.
Therefore, there is a need for a method and apparatus that measures
NO in exhaled air during a tidal breathing manoeuvre in which at
least some of the above mentioned disadvantages are mitigated.
SUMMARY OF THE INVENTION
It has been found that in measurements of nitric oxide (NO) during
tidal breathing over multiple breathing cycles, some exhalations
provide an accurate determination of the NO produced in the lower
respiratory tract, while other exhalations provide an inaccurate
value. The invention provides that in a tidal breathing manoeuvre
involving multiple breaths, a selection is made of those
exhalations or parts of the exhalations where the NO produced in
the lower respiratory tract dominates the NO measurement
contribution from other sources, such as the environment or nasal
cavity of the subject.
Therefore, according to a first aspect of the invention there is
provided a method of determining at least one parameter value
relating to nitric oxide, NO, production in the lower respiratory
tract of a subject, the method comprising obtaining a plurality of
measurements of NO levels in exhaled air and air flow rate during
multiple exhalations of a subject performing tidal breathing;
analyzing the plurality of measurements to identify exhalations
where the NO produced in the lower respiratory tract dominates the
NO contribution from other sources; and determining at least one
parameter value relating to NO in the lower respiratory tract of
the subject from the measurements of NO levels and/or air flow rate
obtained during the identified exhalations.
In a preferred embodiment, the step of analyzing and/or step of
determining comprises using a model describing the flow dependence
of NO levels in exhaled air and wherein the at least one parameter
relating to NO in the lower respiratory tract is a flow independent
parameter of the model. In an alternative embodiment, the step of
analyzing comprises using a model describing the flow dependence of
NO levels in exhaled air and wherein a single flow independent
parameter is used relating to NO in the lower respiratory tract.
The NO produced in the lower respiratory tract has a specific flow
dependence which is disrupted when NO from other sources is
present, so the use of a model describing this flow dependence
allows exhalations where the NO produced in the lower respiratory
tract dominates the NO contribution from other sources to be
identified.
The model in the above embodiments preferably comprises a
two-compartment model, a three-compartment model or a trumpet
model.
In the embodiment in which the model is a two-compartment model,
the exhaled NO, C.sub.E, is given by
ee ##EQU00001## where C.sub.alv is the alveolar concentration,
D.sub.aw is the airway diffusion coefficient, {dot over (V)} is the
air flow rate, the ratio of C.sub.alv/C.sub.w and the value of
D.sub.aw are set to constant values. The wall concentration,
C.sub.w, can then be determined from the measurements of the NO
level and air flow rate. The model can be used for tidal breathing
regimes as it is valid for all relevant flow rates, i.e. from above
a tidal breathing regime to below 50 ml/s. The use of this model is
particularly advantageous during the step of analyzing.
Preferably, in this embodiment, the ratio of C.sub.alv/C.sub.w and
D.sub.aw in the model are set to respective constant values based
on a population value or a previous personal value for the
subject.
In a preferred embodiment in which the model is a trumpet model,
the exhaled NO, C.sub.E, is given by
.times..times..times. ##EQU00002## where {dot over (V)} denotes the
air flow rate, D.sub.ax the axial diffusion constant for Nitric
Oxide, and c.sub.3 and c.sub.4 are positive constants. Furthermore,
the step of analyzing comprises determining values for the maximum
airway wall NO flux, J.sub.aw, from the measurements of the NO
level and air flow rate. This model provides an accurate
description of the flow-dependent NO production on the basis of one
inflammation parameter only, the maximum airway wall flux of NO,
which means that a one-parameter analysis to the tidal breathing
data becomes possible. The use of this model is particularly
advantageous during the step of analyzing.
Preferably, in this embodiment, the parameter D.sub.ax is a
constant value and c.sub.3 and c.sub.4 are set to respective
constant values based on a population value or a previous personal
value for the subject.
In certain embodiments, the step of analyzing comprises dividing
each exhalation into a plurality of exhalation parts; for each
exhalation part, determining values for a flow independent
parameter using the measurements of NO levels and flow rate
obtained during that exhalation part; for each exhalation part,
calculating the spread of the determined values for the flow
independent parameter; and performing a first discarding step in
which any exhalation part where the calculated spread deviates from
a predetermined value by more than a threshold value is discarded;
wherein the step of determining a value for the at least one
parameter relating to NO in the lower respiratory tract of the
subject uses the measurements of NO levels and/or air flow rate for
exhalation parts remaining after the first discarding step. This
results in exhalation parts being discarded where the parameter
value varies more than can be expected for an uncontaminated
exhalation.
Preferably, the threshold value is determined based on the noise in
the measurements of air flow rate and NO level.
In certain embodiments, the step of analyzing further comprises,
for each remaining exhalation part, determining the average value
of the determined values for the flow independent parameter;
identifying the remaining exhalation part having the lowest average
value for the flow independent parameter; and performing a second
discarding step in which any exhalation part whose average value
for the parameter value deviates from the average value for the
parameter value for the identified exhalation part by more than a
threshold value is discarded; wherein the step of determining a
value for the parameter relating to NO in the lower respiratory
tract of the subject uses the measurements of NO levels and/or air
flow rate for the exhalation parts remaining after the second
discarding step. As the exhalation part having the lowest average
for the parameter value is likely to be from the exhalation that
has the least (or no) NO contamination from other sources, it can
be used as a basis for identifying and discarding exhalation parts
where there is consistent NO contamination throughout the
exhalation.
A further aspect of the invention provides a computer program
product comprising computer readable code configured to cause a
computer, processor or computer system to perform the method
described above.
Yet another aspect of the invention provides an apparatus for
determining a value for at least one parameter relating to nitric
oxide, NO, production in the lower respiratory tract of a subject,
the apparatus comprising an NO sensor for taking a plurality of
measurements of the level of NO in air exhaled by the subject
during multiple exhalations of a tidal breathing manoeuvre; a flow
rate sensor for taking a plurality of measurements of the flow rate
of air exhaled during the multiple exhalations of the tidal
breathing manoeuvre; and a processor that is configured to receive
the measurements of NO level and flow rate, analyze the
measurements to identify exhalations where the NO produced in the
lower respiratory tract dominates the NO contribution from other
sources, and determine a value for the parameter relating to NO in
the lower respiratory tract of the subject from the measurements of
NO levels and/or air flow rate obtained during the identified
exhalation parts.
In certain embodiments, the processor is configured to analyze the
measurements by dividing each exhalation into a plurality of
exhalation parts; for each exhalation part, determining values for
a flow independent parameter using the measurements of NO levels
and flow rate obtained during that exhalation part; for each
exhalation part, calculating the spread of the determined values
for the flow independent parameter; and performing a first
discarding step in which any exhalation part where the calculated
spread deviates from a predetermined value by more than a threshold
value is discarded; wherein the step of determining a value for the
parameter relating to NO in the lower respiratory tract of the
subject uses the measurements of NO levels and/or air flow rate for
the exhalation parts remaining after the first discarding step.
In certain embodiments, the processor is further configured to
analyze the measurements by for each remaining exhalation part,
determining the average value of the determined values for the flow
independent parameter; identifying the remaining exhalation part
having the lowest average value of the determined values for the
flow independent parameter; and performing a second discarding step
in which any exhalation part whose average value for the parameter
value deviates from the average value for the parameter value for
the identified exhalation part by more than a threshold value is
discarded; wherein the step of determining a value for the
parameter relating to NO in the lower respiratory tract of the
subject uses the measurements of NO levels and/or air flow rate for
the exhalation parts remaining after the second discarding
step.
BRIEF DESCRIPTION OF THE DRAWINGS
Preferred embodiments of the invention will now be described, by
way of example only, with reference to the following drawings, in
which:
FIG. 1 is a block diagram of a conventional apparatus for measuring
NO levels using a fixed flow rate technique;
FIG. 2 is a block diagram of an apparatus according to the
invention for measuring NO levels using a tidal breathing
technique;
FIG. 3 is a flow chart of an exemplary method according to the
invention;
FIG. 4(a-c) are graphs illustrating how an exhalation can be
divided into parts;
FIG. 5 is a flow chart illustrating the step of analyzing in FIG. 3
in more detail;
FIGS. 6(a) and 6(b) are graphs illustrating measured nitric oxide
levels and calculated nitric oxide levels for a number of
exhalations; and
FIGS. 7(a) and 7(b) show histograms for the exhalations in FIGS.
6(a) and 6(b) respectively.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
An apparatus in accordance with an embodiment of the invention for
measuring NO levels in exhaled air during tidal breathing is shown
in FIG. 2. The apparatus 30 comprises a tube 31 arranged in a
generally `Y` shape with the three ends forming an air inlet 32, an
air outlet 34 and a mouthpiece 36 respectively. A first one-way
valve 38 is provided in the tube 31 between the air inlet 32 and
the mouthpiece 36 and a second one-way valve 40 is provided in the
tube 31 between the mouthpiece 36 and the air outlet 34. The
one-way valves 38, 40 are configured so that air is drawn through
the tube 31 via the air inlet 32 and mouthpiece 36 when the subject
inhales, and air is passed through the tube 31 via the mouthpiece
36 and air outlet 34 when the subject exhales.
A flow rate sensor 41, for instance a differential pressure sensor
that measures a pressure drop over a minimal restriction in the
exhalation path, is provided near to the mouthpiece 36 for
measuring the flow rate of the exhaled air (the flow rate sensor 41
could alternatively be located in the tube 31 between the
mouthpiece and air outlet 34). Instead of measuring a pressure
difference, the flow rate sensor 41 can be based on an ultrasonic
sensor, in which case no restriction is required in the flow path.
A NO sensor 42 for measuring levels of NO in the exhaled air is
connected to a side stream 44 with a connection to the main
exhalation stream preferably close to the mouth piece. The NO
sensor 42 should be capable of measuring low concentrations of NO
at a sufficiently high time resolution in order to capture the
variation in NO levels during the tidal breathing pattern
accurately. In a preferred embodiment, the NO sensor 42 is a
chemiluminescent analyzer. Alternatively, the NO levels can be
measured using a photo-acoustic NO.sub.2 sensor in combination with
a NO-to-NO.sub.2 converter.
It should be noted that the different path lengths to the NO sensor
42 and the flow rate sensor 41 as well as delays in the NO
detection may result in a relative delay in the operation of these
sensors, so there may be a need to apply a correction to the
timings of the relative measurements to ensure that the
measurements correspond to one another.
A processor 46 is connected to the flow rate sensor 41 and NO
sensor 42 so that it receives a time series of measurements of the
flow rate of the exhaled air and the NO levels in the exhaled air.
The processor 46 processes these measurements to determine a value
for one or more flow independent parameters related to NO
production in the lower respiratory tract of the subject, as
described further below.
When the apparatus 30 is in use, the subject breathes normally and
NO levels and corresponding flow rates are recorded for a plurality
of exhalations. Preferably measurements are acquired during a
measurement period of about 30 seconds to one minute to enable
enough NO and flow measurement data for the analysis.
The processor may be coupled to a memory 47 for storing data. If
the subject under test has previously been tested the memory 47 may
store some personal information about that subject and may store
values for various model parameters which are appropriate for that
subject. The memory 47 may also store general or specific
population averaged values for various model parameters. The memory
47 may be integrated with the processor 46 or may be a removable
memory apparatus.
A NO filter 48 can be provided in the tube 31 between the air inlet
32 and the first one-way valve 38 that removes NO from the air
drawn into the apparatus 30 from the surrounding environment when
the subject inhales.
Unlike with the fixed flow rate apparatus 2 shown in FIG. 1, it is
not essential to provide a flow restrictor in the tube 31 between
the second one-way valve 40 and the air outlet 34 as in the fixed
flow rate apparatus 2. However, a small restriction can be included
to increase the pressure and thus the concentration of NO in the
air sampled by the NO sensor 42, thereby increasing the accuracy of
the processor output.
Although not shown in FIG. 2, where the apparatus 2 provides
measurements of NO levels in real-time or near real-time, the
apparatus 2 could be provided with a feedback unit for providing
audio and/or visual feedback to the subject once a sufficient
number of breaths or an acceptable number of data points have been
collected.
The operation of the processor 46 according to the invention will
now be described in more detail with reference to the flow charts
shown in FIGS. 3 and 4. Firstly, in step 101 of FIG. 3, the
processor 46 obtains a plurality of measurements of NO levels and
the corresponding air flow rates covering a number of exhalations
by a subject performing a tidal breathing manoeuvre.
As described above, it has been found that some exhalations during
tidal breathing provide an accurate representation of the NO
produced in the lower respiratory tract, while other exhalations
during tidal breathing are contaminated with NO from other sources
and provide an inaccurate value. So, in accordance with the
invention, the processor 46 analyses the measurements to identify
those exhalations or parts of the exhalations where the NO produced
in the lower respiratory tract dominates the NO measurement
contribution from other sources, such as the environment or nasal
cavity of the subject (step 103).
The processor 46 then uses the measurements for part or all of the
identified exhalations (i.e. those exhalations where the NO
produced in the lower respiratory tract dominates the NO
measurement contribution from other sources) to determine values
for one or more flow independent parameters related to NO
production in the lower respiratory tract of the subject (step
105).
In preferred embodiments of the invention, the identification in
step 103 and subsequent determining in step 105 can make use of a
model or a combination of models that describe the production,
diffusion and/or removal of NO in the lower respiratory tract of
the subject. In the identification step, use can be made of the
fact that the NO produced in the lower respiratory tract has a
specific flow dependence which is disrupted when NO from other
sources is present. Preferably a model with a single free parameter
is used in the identification step and statistical measures are
applied to identify those parts of the exhalation where the NO from
the lower respiratory tract dominates. During the determining step
all identified parts of the exhalations are used in an analysis
with either the same single parameter model or a model with more
free parameters.
Various different models of NO production and diffusion in the
lungs are known and can be used as the model describing flow
dependence of exhaled NO. Key elements in these models are: i) a
description of the geometry of the lung system, often in simplified
compartment form, ii) NO generation, and iii) NO diffusion. For
instance a two-compartment model of NO exchange dynamics represents
the lungs by a rigid airway compartment and a flexible alveolar
compartment--see for example Tsoukias et al. "A two-compartment
model of pulmonary nitric oxide exchange dynamics" J. Appl.
Physiol, Vol. 85, pp 653-999, 1998. A three compartment model is
described in "Characterizing airway and alveolar nitric oxide
exchange during tidal breathing using a three-compartment model",
P. Condorelli et al., J. Appl. Physiol. Vol 96, pp 1832-1842, 2004.
Another model is a trumpet model with axial diffusion which takes
account of the trumpet shape of the airways and assumes that axial
diffusion is the dominating NO diffusion mechanism--see
US2007/0282214 or P. Condorelli et al., J. Appl. Physiol. Vol 102,
pp 417-425, 2007 for example. The trumpet model with axial
diffusion can provide a good description of the flow dependent NO
production in the lungs but is mathematically more complex than the
two and three compartment models and requires use of approximate
analytical solutions or numerical solutions. All the aforementioned
models form approximations to a more general model describing the
generation and transport of various gasses in the airway system by
a partial differential convective diffusion equation where the
3-dimensional asymmetric airway structure is mapped into the flow
through an axially symmetric tube with a varying diameter.
The models describing the flow dependence of exhaled NO generally
are based on various flow independent parameters. The two
compartment model for example has three flow independent
parameters, the steady state alveolar concentration, the airway
wall diffusing capacity and the airway wall concentration
(alternatively, instead of the airway wall concentration parameter,
the maximum airway wall flux of NO can also be used). The steady
state alveolar concentration and airway wall concentration will
vary with the severity of any airway inflammation whereas the
airway wall diffusing capacity is a gas diffusion parameter related
to the transfer of NO between airway wall and gas stream and
differs only slightly for healthy and asthmatic people. The
Condorelli approximation to the trumpet model with axial diffusion
has three flow independent parameters, two of which vary with the
severity of inflammation of the lungs, i.e. the steady state
alveolar concentration and maximum airway wall flux of NO and one
describing the axial gas diffusion. Although the flow-independent
parameters linked to the severity of inflammation from the
two-compartment model and axial diffusion dominated trumpet model
have similar names their actual values are model dependent and
values can only be converted in a simple way within a certain flow
range.
In general, values for the various parameters in the model
describing the NO production in the lower respiratory tract are not
known in advance for a specific subject. Therefore, in embodiments
of the invention, the model used by the processor 46 can be set-up
in a way such that flow dependent NO production is described to a
reasonable accuracy by a single unknown parameter.
This can be achieved by setting parameters with small variability
to average values leaving a single inflammation related parameter
as the remaining unknown parameter. For example, at least one of
the parameters of the model relating to gas diffusion and/or at
least one other parameter related to inflammation can be set to a
constant value. At least one of the parameters may be set to
population average values, i.e. an average value that has
previously been determined for the population. For some parameters,
different population average values may exist based on gender, age,
etc. and the appropriate value for the subject can be chosen.
Setting these parameters to population averages obviously results
in some inaccuracy but it has been found that sufficiently accurate
values for the flow independent parameters may still be obtained.
Additionally or alternatively at least one of the flow-independent
parameters may be set to a personal value previously obtained or
estimated for the particular test subject. A value for one or more
flow independent parameters could be determined for the subject and
used in all successive measurements.
The model therefore incorporates one or more flow independent
parameters which vary with inflammation that are determined from
the measurements of the level of exhaled NO and the corresponding
flow rate. The remaining parameters are either set as constants, a
population average relevant for the subject or a previously
estimated or determined value for the subject.
The two compartment model mentioned above describes the lungs as a
cylindrical rigid airway compartment with a volume of around 150 ml
and a flexible alveolar compartment. The airway compartment is
described by two parameters, the airway diffusing capacity and
either the airway wall concentration of NO or maximum airway wall
flux of NO. The alveolar compartment is described by a single
parameter, the steady state alveolar concentration of NO. The
exhaled NO concentration C.sub.E as a function of the flow {dot
over (V)} according to the two compartment model is given by:
ee ##EQU00003##
Thus, the exhaled NO concentration depends on the wall
concentration C.sub.w and alveolar concentration C.sub.alv weighted
by terms that depend on the airway diffusion coefficient D.sub.aw
and the flow. The analytical expression is valid for all relevant
flows i.e. from above the tidal breathing regime to below 50
ml/s.
In clinical studies it has been observed that the airway diffusing
capacity is not directly related to inflammation severity.
Therefore the airway diffusing capacity can be estimated based on
population averages. In case the tidal breathing NO measurement
device is used for repeated measurements of an already diagnosed
asthmatic individual, a population average value for asthmatic
persons of D.sub.aw can be used. Alternatively the airway diffusing
capacity for a particular subject may have been derived previously,
for instance from different measurements, and may be entered into
the processor 46 or obtained from memory 47.
In one embodiment, the steady-state NO concentration in the
alveolar compartment, C.sub.alv, can also be set to a separately
determined individual value, which means that the processor 46 can
determine values for the remaining flow independent inflammation
related parameter (wall concentration C.sub.w) using the
measurements of the NO levels (C.sub.E) and air flow rate ({dot
over (V)}).
However, whilst the two compartment model can give satisfactory
results with prior knowledge of the alveolar concentration, a model
including axial diffusion is currently preferred as it can provide
a sufficiently accurate description of the flow-dependent NO
production on the basis of one inflammation parameter only, which
is the maximum airway wall flux of NO. The axial gas diffusion
constant is to a large extent a general gas diffusion constant.
Application of a model where the inflammation is described by one
dominating parameter has the main advantage that a one-parameter
analysis to the tidal breathing data becomes possible. The latter
is an advantageous feature during the final analysis of the data
within the selected exhalations or exhalation parts, but it forms a
highly preferred analysis approach for the first stage of selection
of contaminated and non-contaminated parts.
The trumpet model as, for instance, described in US2007/0282214 is
an example of a model including axial diffusion, maximum airway
wall flux of NO and a steady state alveolar concentration. This
model can be further extended to include the airway diffusing
capacity and for instance a maximum airway wall flux of NO that
depends on the axial position in the airway tree. It should be
noted that the values of the maximum airway wall flux of NO, steady
state alveolar NO concentration and NO diffusing capacity for a
model including axial diffusion cannot be directly compared to
their value in for instance a two-compartment model without axial
diffusion.
Trumpet models including axial diffusion are defined by a
differential equation, a source term describing the NO production,
boundary conditions to the alveolar and mouth region and a
description of the trumpet shape. A general solution is not known
but a numerical solution can be obtained when all the parameter
values are known. A determination of one or more parameter values
from experimental data becomes only possible on basis of an
approximate analytical solution or a time-consuming and complex
iterative numerical procedure.
US2007/0282214 discloses a linear approximation of the
flow-dependent NO production for a trumpet model including a
maximum airway wall flux of NO, steady state alveolar value and
axial diffusion. The linear approximation is valid in the
flow-range of 100-250 ml/s. Most tidal breathing manoeuvres are
within this flow range but for some subjects, tidal breathing
involves higher flows.
Comparing numerical solutions and analytical approximations for
typical values for the trumpet model parameters, the present
inventors have found that the following analytical expression
describes the NO production C.sub.E as a function of flow {dot over
(V)} for flows of 25 ml/s and above quite accurately:
.times..times..times..times. ##EQU00004## where {dot over (V)}
denotes the flow rate of exhaled air, D.sub.aw the airway wall
diffusion coefficient and D.sub.ax the axial diffusion constant for
Nitric Oxide. C.sub.alv is a flow independent contribution relating
the steady state alveolar NO concentration. c.sub.1, c.sub.2,
c.sub.3 and c.sub.4 are positive constants which are derived from
fits to numerical solutions of a differential equation describing
nitric oxide production, convection and diffusion in the airway
tree. In one model, c.sub.1 may have a value of around 1, c.sub.2
may have a value of 0.4, c.sub.3 may have a value around 2200
ml/cm.sup.2 and c.sub.4 may have a value of around 0.25.
For flows around 50 ml/s and above, and the time scale involved in
tidal breathing, D.sub.aw and the steady state alveolar value
C.sub.alv can be set to zero. 0.23 cm.sup.2/s can be used as a
typical value for D.sub.ax (The Properties of Gases and Liquids, RC
Reid et al., New York: McGraw-Hill, 1988).
J.sub.aw is the maximum airway wall NO flux, a flow independent
parameter which is particular to the subject and which the
processor 46 determines from the measurements of exhaled NO level
and flow rate.
The approximated analytical solution given above is based on the
finding that (a product) of diffusion terms of the form:
.times. ##EQU00005## with k.sub.1 and k.sub.2 constant, provides a
good description of the flow dependent NO production in the trumpet
shaped airway. An analytical approximation is very powerful in the
analysis of the measurement data because it enables a simple and
fast determination of one or more flow-independent parameter(s)
from experimental data.
In one embodiment, where the apparatus 30 according to the
invention is to be used in a professional care setting for
evaluating the lung inflammation of various subjects, the
flow-independent parameters D.sub.aw and C.sub.alv can be set to
population averaged values leaving J.sub.aw as the single unknown
inflammation related parameter. Alternatively, where the apparatus
30 is to be used by an individual subject (i.e. by a subject
monitoring their asthma in a home setting, say), the values of
D.sub.ax, D.sub.aw and C.sub.alv for the subject can be derived
following analysis of the subject by a pulmonologist (perhaps by
using the conventional fixed-flow exhalation measurement
technique). As a further alternative, following diagnosis of
asthma, the parameters D.sub.ax and D.sub.aw can be set to
population averaged values for people with asthma.
For the two compartment model, an analysis with a single
inflammation related parameter becomes possible by using a fixed
ratio of the alveolar concentration and the wall concentration
C.sub.alv/C.sub.w (or C.sub.alv/J.sub.aw). This ratio can either be
based on a population average or derived from axial diffusion i.e.
a by linking the two-compartment model parameters to the trumpet
model parameters in the tidal breathing flow range.
Step 103 of FIG. 3 will now be described in more detail with
reference to the graphs in FIG. 4 and the flow chart in FIG. 5.
For the analysis and determining steps, each exhalation is split
into parts (for example initial, intermediate and final parts) in a
predefined way. A preferred embodiment is shown in FIG. 4. The
measured eNO and flow profiles for exhalation i are shown in FIGS.
4(a) and 4(b) as a function of time. Any time delay between the eNO
and flow measurements resulting from gas transport, dead volumes
and NO sensor delay should be taken into account. The exhalation
volume versus time as shown in FIG. 4(c) is obtained by integration
of the flow profile from the beginning at t.sup.i.sub.b to the end
t.sup.i.sub.e. The maximum exhaled volume V.sup.i.sub.max for
exhalation i is reached at t.sup.i.sub.e. Subsequently, to split
the profile for an exhalation into three parts, time t.sup.i.sub.1
indicating the end of an initial part of the exhalation and time
t.sup.i.sub.2 indicating the start of a final part of the
exhalation can be determined corresponding to for instance 30% and
80% of the maximum exhaled volume respectively. The first part of
the eNO and flow profile now corresponds to time frame
t.sup.i.sub.b-t.sup.i.sub.1, the second part to
t.sup.i.sub.1-t.sup.i.sub.2 and the third part to
t.sup.i.sub.2-t.sup.i.sub.e. If advantageous, the fractions of the
maximum volume or the number of parts can be chosen
differently.
FIG. 5 shows the analysis steps in more detail. Firstly, in step
120 all the exhalations are divided into the predefined parts as
shown in FIG. 4. In step 121 of FIG. 5, the processor 46 discards
all parts of the first exhalation in the tidal breathing manoeuvre,
and some parts of each subsequent exhalation, for instance the
initial and final parts. It can be seen in the graphs of FIGS. 6(a)
and (b) in which the exhaled NO levels are plotted against time
that the measured NO levels (represented by the dashed line) are
often higher at the start of an exhalation. A small increase in
agreement with the models, is expected due to the increased
residence time in the airways around the transition from inhalation
to exhalation. However, larger peaks are often observed at the
beginning and end of the exhalation and are due to nasal NO
contamination during the low exhalation flows around the transition
from inhalation to exhalation and exhalation to inhalation.
Therefore it is useful to discard the measurements at the beginning
and end of each exhalation from subsequent analysis. "Discarding"
measurements or parts can comprise deleting the measurements for
that part from the memory 47 or labeling the measurements for that
part in the memory 47 appropriately so that they are not used
during later processing steps. Each exhalation part that is not
discarded in step 121 is referred to as a remaining part in the
following explanation of FIG. 5.
Then, in step 123, the processor 46 applies the measurements of the
exhaled NO level and flow rate for the remaining (i.e.
non-discarded) part or parts of each exhalation to the selected
model to determine values for the flow-independent parameter. For
example, if the trumpet model described above is used, the
processor 46 will determine values for the maximum airway wall NO
flux, J.sub.aw in this step.
Next, for each exhalation part, the processor 46 determines the
variation or spread in the parameter value across the exhalation
part (step 125). Techniques for determining the variation or spread
of a set of data values are well known in mathematics and will not
be described in any further detail herein.
It is expected that there will be a relatively small spread in the
parameter value across the exhalation part when the measurement of
the exhaled NO is dominated by NO generated in the lower
respiratory tract. In particular, for an uncontaminated exhalation,
the spread in the parameter value should roughly correspond to the
noise in the flow rate and NO measurements and the inaccuracy that
arises from approximating values for the other parameters in the
model. Therefore, where the spread in the parameter value for an
exhalation part exceeds a predetermined value, the processor 46
discards that exhalation part from further analysis (step 127). For
instance, the exhalation part can be discarded when the standard
deviation is larger than 2 times the standard deviation based on
the noise level in the NO and flow measurement.
In some embodiments of the invention, step 127 can conclude the
analysis step (step 103 of FIG. 3) and the processor 46 can use the
measurements for exhalations having remaining parts to determine
the required parameter values in step 105 of FIG. 3.
However, in other embodiments of the invention, the processor 46
can carry out additional analysis to determine whether any further
(parts of the) exhalations need to be excluded. In particular, in
step 129, the processor 46 determines the average magnitude of the
parameter value for each exhalation part remaining in the
analysis.
It is understood that the exhalation(s) having the parameter values
corresponding to the lowest NO values are, most likely, not
contaminated. Therefore, the average magnitude of the parameter
value for a specific remaining exhalation part is compared to the
average magnitude of the parameter value for other remaining
(non-discarded) parts, and where the average parameter value
deviates significantly from this value that exhalation part is
discarded from further analysis.
In particular, in step 131, the processor 46 identifies the
remaining part with the parameter value corresponding to the lowest
exhaled NO measurements, and, in step 133, discards any other
remaining parts whose average magnitude for the parameter value
deviates from the average magnitude of the parameter value for the
identified part by more than a threshold value. For instance, an
exhalation part can be discarded when the average parameter value
for that part differs from the average parameter value for the
identified exhalation part by more than 0.3 times the average
parameter value for the identified exhalation part.
The processor 46 can then use the measurements for the remaining
parts of the exhalations to determine the required parameter values
in step 105 of FIG. 3.
In further embodiments of the invention, as it is possible for the
removal of environmental and nasal NO in the respiratory tract
during inhalation to be described by a model representing the
mixing and diffusion process in the alveolar part, it is possible
for the processor 46 to take the inhalation into account in order
to determine whether an exhalation or an extended initial part of
an exhalation has to be discarded from further analysis.
The operation of the processing method described above can be seen
in FIGS. 6(a) and (b). These graphs show the exhaled NO measurement
data for two separate tidal breathing manoeuvres comprising five
exhalations. The measurements of the exhaled eNO are represented by
the dashed lines.
In this illustrated embodiment, the processor 46 is using the
trumpet model and values for all of the flow independent parameters
have been separately determined and the measurements of flow rate
are used as the input to the model in order to calculate expected
values for the exhaled NO measurements.
Therefore, following the method in FIG. 5 above, the processor 46
determines values for the exhaled NO using the flow rate
measurements in the remaining parts and the model (the determined
values are shown in FIGS. 6(a) and (b) by the solid lines).
It is clear from FIG. 6 that significant deviations occur between
the measured NO levels and the expected NO levels for the fourth
exhalation in FIG. 6(a) and the first exhalation in FIG. 6(b). By
following the steps in FIG. 5, the processor 46 will discard the
measurements for these exhalations from subsequent analysis.
In the fourth exhalation of FIG. 6(a), a deviation from the
determined NO value is seen which is large in the beginning of the
exhalation, and becoming smaller towards the end of the exhalation.
In this case, a small percentage of the air has probably been
inhaled through the nose and has not reached the lower parts of the
lung that are effective in NO removal.
The offset in the first exhalation in FIG. 6(b) is understood as
being due to the shallow inhalation and incomplete removal of NO in
the alveolar part of the lung of environmental or nasal NO inhaled
from a previous breath cycle.
FIG. 7 illustrates the method by means of histograms. By using the
two-compartment model or trumpet model with J.sub.aw as the single
unknown parameter (where J.sub.aw is given by D.sub.awC.sub.w in
equation (1)), the value of J.sub.aw can be determined using the
exhaled NO and flow rate measurements within a certain range of
exhaled volumes (for instance 30-80% of the maximum exhaled volume
for each exhalation) and a histogram can be compiled from the
J.sub.aw values for every exhalation (or exhalation part). FIGS.
7(a) and (b) show the histograms for the measurement data shown in
FIGS. 6(a) and (b) respectively.
In the histograms shown, bins of 0.15 pico-liters/second (pl/s) are
used. The values of J.sub.aw for each exhalation part are put into
the relevant bins, and the lines in the graphs represent individual
exhalation parts shown in FIG. 6.
Exhalation parts can be accepted as non-contaminated based on the
width of the histogram for that exhalation part being within a
certain value and/or the average value for J.sub.aw in that
exhalation part being within a certain range of the overall average
J.sub.aw (or minimum average J.sub.aw) of all the remaining
exhalation parts. For example, it can be seen in FIG. 7(a) that the
spread in J.sub.aw values for the remaining part of the fourth
exhalation is large, so without knowledge of the subject's J.sub.aw
parameter, this exhalation can be discarded from further
analysis.
Although the spread in J.sub.aw values for the remaining part of
the first exhalation in FIG. 7(b) is slightly higher than the
spread for the remaining parts of the other exhalations, this might
not be sufficient to take a decision to discard this exhalation. In
this case, it might be necessary to perform a comparison with the
average values for the other exhalation parts in order to determine
whether this exhalation should be discarded.
It will be appreciated that the invention described above can be
used with currently available eNO measurement systems, provided
that the sensors in these systems have a sufficient time resolution
(i.e. a short enough response time) to measure the NO patterns
during tidal breathing. As indicated above, such sensors include
chemiluminescent analyzers.
Although the invention has been described in terms of a method
performed by a processor in a measurement apparatus, it will be
appreciated that the invention can be performed by a suitably
programmed computer and therefore the invention can also comprise a
computer program which, when run on a suitable computer or computer
system and given the plurality of measurements as a data input,
performs the method described above. The computer program may be
stored on a computer readable storage medium, for example a hard
disk, an optical disk or a memory card.
Thus, there is provided a method and apparatus that can measure NO
in exhaled air during a tidal breathing manoeuvre and that
mitigates the problems with contamination of the exhaled air with
inhaled NO from the nasal cavity.
While the invention has been illustrated and described in detail in
the drawings and foregoing description, such illustration and
description are to be considered illustrative or exemplary and not
restrictive; the invention is not limited to the disclosed
embodiments.
Variations to the disclosed embodiments can be understood and
effected by those skilled in the art in practicing the claimed
invention, from a study of the drawings, the disclosure, and the
appended claims. In the claims, the word "comprising" does not
exclude other elements or steps, and the indefinite article "a" or
"an" does not exclude a plurality. A single processor or other unit
may fulfill the functions of several items recited in the claims.
The mere fact that certain measures are recited in mutually
different dependent claims does not indicate that a combination of
these measures cannot be used to advantage. A computer program may
be stored/distributed on a suitable medium, such as an optical
storage medium or a solid-state medium supplied together with or as
part of other hardware, but may also be distributed in other forms,
such as via the Internet or other wired or wireless
telecommunication systems. Any reference signs in the claims should
not be construed as limiting the scope.
* * * * *